Chemical ablation formulations and methods of treatments for various diseases

ABSTRACT

Embodiments of the present invention are directed to the treatment of hypertension, diabetes, obesity, heart failure, end-stage renal disease, digestive disease, urological disease, cancers, tumors, pains, asthma, pulmonary arterial hypertension, and chronic obstructive pulmonary disease by delivering of an effective amount of formulations at desired temperature to target tissue. The formulations include gases, vapors, liquids, solutions, emulsions and suspensions of one or more ingredients. The temperature may enhance safety and efficacy of the formulations for the treatments. The amounts of the formulation and/or energy are effective to injury or damage the tissues to have a benefit of symptom relive.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/419,587, filed May 22, 2019 continuation of U.S. application Ser. No.14/438,411, filed Apr. 24, 2015, which claims the benefit of U.S.National Stage Filing under 35 U.S.C. 371 from International ApplicationNo. PCT/US2013/067382, filed Oct. 30, 2013, which claims benefit of U.S.Provisional Application No. 61/796,118, filed Nov. 2, 2012, ApplicationSer. No. 61/797,647, filed Dec. 12, 2012, Application Ser. No.61/848,483, filed Jan. 4, 2013, and Application Ser. No. 61/849,928,filed Feb. 5, 2013, which are hereby incorporated herein by reference intheir entirety.

TECHNICAL FIELD

Embodiments of the present invention relate to chemical ablationformulations, combination of thermal and chemical ablations, and methodsof treatments for diseases, such as hypertension, diabetes, obesity,heart failure, end-stage renal disease, digestive diseases, urologicaldiseases, cancers, tumors, pains, asthma, pulmonary arterialhypertension, and chronic obstructive pulmonary disease (COPD). Theformulations include gases, vapors, liquids, solutions, emulsions, andsuspensions of one or more ingredients. The methods involve chemicalablation by delivering the formulations or/and thermal energy to thetarget of diseased tissues of human body.

BACKGROUND

Hypertension, or high blood pressure, is a major global public healthconcern. An estimated 30-40% of the adult population in the worldsuffers from this condition. Furthermore, its prevalence is expected toincrease, especially in developing countries. Diagnosis and treatment ofhypertension remain suboptimal and most of patients cannot attainadequate blood-pressure control to guideline target values. Thus, thedevelopment of new approaches for the management of hypertension isneeded, especially those patients with so-called resistant hypertension.These patients fail to control blood pressure to the target despitemultiple drug therapies at the highest tolerated dose.

Hypertension is caused by hyperactive renal sympathetic nerves. Renalsympathetic efferent and afferent nerves run generally longitudinallyalong the outside of arteries leading from the aorta to the kidneys.These nerves are critically important in the initiation and maintenanceof systemic hypertension. It has been shown that by severing thesenerves, blood pressure can be reduced. Exemplary experiments have shownthat denervation of the renal sympathetic nerves in rats withhyperinsulinimia-induced hypertension would reduce the blood pressure tonormotensive levels as compared to controls [Huang W-C, et al.Hypertension 1998; 32:249-254].

While renal denervation had been performed with surgical methods in thepast, more recently a catheter-based therapy to heat and destroy thenerves from within the renal artery using radio-frequency ablation hasbeen studied. A human trial of the RF-ablation catheter method has alsobeen performed, with reported reduction in blood pressure in patientsenrolled in the catheter treatment arm of the study [Krum H, et al.Lancet 2009; 373(9671):1228-1230].

Benign prostatic hyperplasia is a non-cancerous enlargement of theprostate gland, affecting more than 50% percent of men over the age of60. The prostate early in life is the size and shape of a walnut andweight about 20 grams. Prostate enlargement appears to be a normalprocess. With age, the prostate gradually increases in size to twice ormore its normal size. As the prostate grows, it presses against andnarrows the urethra, causing a urinary obstruction that makes itdifficult to urinate.

Chronic obstructive pulmonary disease (COPD) is a term used to classifytwo major airflow obstruction disorders: chronic bronchitis andemphysema. Approximately 16 million Americans have COPD, 80-90% of themwere smokers throughout much of their lives. COPD is a leading cause ofdeath in the U.S. Chronic bronchitis is inflammation of the bronchialairways. The bronchial airways connect the trachea with the lungs. Wheninflamed, the bronchial tubes secrete mucus, causing a chronic cough.Emphysema is an overinflation of the alveoli, or air sacs in the lungs.This condition so causes shortness of breath.

Asthma is a chronic respiratory disease characterized by inflammation ofthe airways, excess mucus production and airway hyper responsiveness,and a condition in which airways narrow excessively or too easilyrespond to a stimulus. Asthma episodes or attacks cause narrowing of theairways, which make breathing difficult. Asthma attacks can have asignificant impact on a patient's life, limiting participation in manyactivities. In severe cases, asthma attacks can be life threatening.Presently, there is no known cure for asthma.

Pulmonary arterial hypertension (PAH) is defined as a group of diseasescharacterized by elevations of mean pulmonary artery pressure and aprogressive increase in pulmonary vascular resistance resulting in rightheart failure and premature death. Recent targeted therapies haveadvanced the treatment. However, there is no cure for PAH and it remainsa life-threatening disorder. The preliminary safety and efficacy ofpulmonary artery radio-frequency denervation for PAH patients have beenreported.

Chronic sinusitis is an inflammation of the membrane lining of one ormore paranasal sinuses. Chronic sinusitis lasts longer than three weeksand often continues for months. In cases of chronic sinusitis, there isusually tissue damage. According to the Center for Disease Control(CDC), thirty seven million cases of chronic sinusitis are reportedannually.

Radio frequency (RF) ablation has been used in treatments ofhypertension, asthma and chronic obstructive pulmonary disease (COPD).While the use of catheter-based radiofrequency (RF) denervation appearsto have a therapeutic effect, it is unknown what long-term implicationswill arise from the permanent damage caused to the vessel wall andnerves by the RF procedure. Radiofrequency energy denervates the vesselby creating heat in the vessel wall. The RF probe contacts the innerlining of the artery and the RF energy is transmitted through thetissue. It lacks fine control. It may cause damage to the endotheliumand smooth muscles, resulting in vessel injury and occlusion. TheSYMPLICITY HTN-2 trial shows that there are three groups of patients.About 10% are non-responders; 39% are excellent responders, with bloodpressure going below 140 mmHg; and in between there are 50% of patientswith some response, with at least 10 mmHg drops, but at the moment we donot know what the clinical relevance of this drop is. The safety andefficacy need to improve for most of patients with hypertension.

A variety of ablative techniques have been developed to complement thetraditional surgical and oncologic approaches used in treating tumors.These techniques including transarterial chemoembolization, percutaneousablation with chemicals such as alcohol or acetic acid, or percutaneoustreatment with radiofrequency ablation or cryotherapy. The regional andlocal ablative techniques used in the treatment of hepatic tumors havebeen studied extensively and they have been used in treating a varietyof other tumors recently. Systemic chemotherapy and external beamradiation therapy have limitations due to poor tumor response andtoxicity. New ablation methods are needed to improve safety and efficacyof treatments.

SUMMARY

Disclosed are methods for the treatment of diseases, such ashypertension, diabetes, obesity, heart failure, end-stage renal disease,digestive disease, urological disease, cancers, tumors, pains, asthma,pulmonary arterial hypertension, and chronic obstructive pulmonarydisease (COPD). In some embodiments, the methods involve delivering aneffective amount of a formulation to target diseased tissues. Theformulation can comprise gases, vapors, liquids, solutions, emulsions,or suspensions of one or more ingredients. The methods involvedelivering the formulations at various temperatures to tissues of humanbody. The temperature may enhance safety and efficacy of theformulations for the treatments. Suitable temperature can be in therange of −40 to 140° C., preferable in the range of −30 to 100° C., mostpreferable in the range of −30 to 80° C. The pressure of the formulationinfused is higher than body lumen pressure (1 ATM). The pressure rangeof the formulation infused to the target tissue is from 1 to 12 ATM, or1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM. The formulation is oneof binary, ternary, four component, or more than four componentformulations. The delivery system can be a percutaneous or less invasivedelivery method. In some embodiments, the formulation comprises one ormore ingredients that enhance absorption and penetration into the nervesof body lumens.

In some embodiments, the methods involve delivering of an effectiveamount of energy and formulations to target nerves. For example, theenergy can be selected from the group consisting of radiofrequency,cryoablation, microwave, laser, ultrasound, and high-intensity focusedultrasound energies. As above, the formulations can include gases,vapors, liquids, solutions, emulsions, and suspensions of one or moreingredients. The methods can involve the combination of thermal andchemical ablation, their formulations, and methods for treatments ofhypertension, diabetes, obesity, heart failure, end-stage renal disease,digestive disease, urological disease, asthma, pulmonary arterialhypertension and chronic obstructive pulmonary disease (COPD) by thermaland chemical ablations to nerves of human body at various temperatures.The thermal energy may enhance safety and efficacy of the chemicalablation for the treatments. The chemical ablation may improve safetyand efficacy of thermal ablation for the treatments by lowing ablationtemperature and time. The temperature can be in the range of −40 to 140°C., preferable in the range of −30 to 100° C., most preferable in therange of −30 to 80° C. The pressure of the formulation infused is higherthan body lumen pressure (1 ATM). The pressure range of the formulationinfused to the target tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to5 ATM, preferred 1 to 3 ATM. The formulation can be one of binary,ternary, four component, or more than four component formulations. Thedelivery system can be a percutaneous less invasive delivery catheter.The formulation delivery catheter can be a needle based catheter. Theformulation delivery catheter can also be a balloon based catheter. Theballoon based catheter can have single or double balloons. Theformulation delivery catheters can be an infusion catheter. The energydelivery catheter can be selected from the group consisting ofradiofrequency, cryoablation, microwave, laser, ultrasound, andhigh-intensity focused ultrasound delivery catheters. In someembodiments, the disclosed methods provide a combination of thermalenergy and formulation comprising one or more ingredients that enhanceabsorption and penetration into the nerves of body lumens.

In some embodiments, the disclosed methods improve safety and efficacyof radiofrequency ablation by increasing ablation size, while minimizingthe risks for complications that can arise during the heating. Examplesof such complications include thrombus formation, steam pops, bubbling,charring on the lesion, restenosis, fibrosis in the media and theadventitia, and others related to catheter manipulation (i.e.,perforations). Spot thermal ablation (RF ablation) is not uniform and itdoes not reach to the nerves in adventitia. Partially spot RF ablationleads to low efficacy (low blood pressure drops). Complications can beminimized by reducing the electrode size (leading to passive cooling viathe blood flow) and cooling the electrode through active fluids, coolingeither internally (closed-loop) or externally (open-loop). Cooling theelectrodes increases energy delivery into the nerve tissue. In oneembodiment of externally cooling (open-loop), the chemical formulationcan replace the active cooling fluids. The disclosed formulation can beused not only for cooling electrodes, but also used for chemicalablation. Therefore, the chemical ablation formulation can be deliveredduring, before, and after the thermal ablations. Thermal ablationsinclude radiofrequency, cryoablation, microwave, laser, ultrasound, andhigh-intensity focused ultrasound ablations.

In some embodiments, the ingredient of the formulation is chosen fromwater, saline, hypertonic saline, phenol, methanol, ethanol, absolutealcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol,glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide,ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropylacetate, ethyl lactate, urea, lipiodol, surfactant, derivatives andcombinations thereof.

In some embodiments, the ingredient of the formulation comprises one ormore gases. Suitable gases include oxygen, nitrogen, helium, argon, air,carbon dioxide, nitric oxide, vapors of organic and inorganic compounds,water, phenol, methanol, ethanol, absolute alcohol, isopropanol,propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid,lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methylacetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate,derivatives and combinations thereof.

In some embodiments, the ingredient of the formulation comprises one ormore surfactants. Examples of surfactants include PEG laurate, Tween 20,Tween 40, Tween 60, Tween 80, PEG oleate, PEG stearate, PEG glyceryllaurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryllaurate, plyglyceryl oleate, polyglyceryl myristate, polyglycerylpalmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEGsorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauraylether, octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrosemonolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, benzalkoniumchloride, benzethonium chloride, docecyl trimethyl ammonium bromide,sodium ricinoleate, dioctyl sodium sulfosuccinate, sodium laurylsulfate, sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride,and dialkylesters of sodium sulfonsuccinic acid, organic acid, salts ofany organic acid and organic amine, polyglycidol, glycerol,multiglycerols, galactitol, di(ethylene glycol), tri(ethylene glycol),tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol)oligomers, di(propylene glycol), tri(propylene glycol), tetra(propyleneglycol, and penta(propylene glycol), poly(propylene glycol) oligomers, ablock copolymer of polyethylene glycol and polypropylene glycol,Pluronic, Pluronic 85, and derivatives and combinations thereof.

In some embodiments, the formulation comprises at least one oil, fattyacid, or lipid. Examples include soybean oil, vegetable oil, flower oil,animal oil, marine oil, butterfat, coconut oil, palm oil, olive oil,peanut oil, fish oil, butanoic acid, hexanoic acid, octanoic acid,decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid,octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoicacid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoicacid, tocotrienol, butyric acid, caproic acid, caprylic acid, capricacid, lauric acid, myristic acid, palmitic acid, palmitoleic acid,stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenicacid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid,natural or synthetic phospholipids, mono-, di-, or triacylglycerols,cardiolipin, phosphatidylglycerol, phosphatidic acid,phosphatidylcholine, alpha tocoferol, phosphatidylethanolamine,sphingomyelin, phosphatidylserine, phosphatidylinositol,dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,phosphatidylethanolamines phosphatidylglycerols, sphingolipids,prostaglandins, gangliosides, neobee, niosomes, and derivatives thereof.

In some embodiments, the formulation includes one or more therapeuticagents or drugs for nerve denervation. Examples of therapeutic agentsinclude sodium channel blockers, tetrodotoxin, saxitoxin, decarbamoylsaxitoxin, vanilloids, neosaxitoxin, lidocaine, conotoxins, cardiacglycosides, digoxin, glutamate, staurosporine, amlodipine, verapamil,cymarin, digitoxin, proscillaridin, quabain, veratridine, domoic acid,oleandrin, carbamazepine, aflatoxin, guanethidine, and guanethidinesulfate. In another embodiment, the formulation includes one of thecontrast agents for imaging nerve denervation. The contrast agentincludes iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynoliodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide,ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and theirderivatives.

In some embodiments, the formulation includes an azeotrope. An azeotropeis a mixture of two or more ingredients in such a way that itscomponents cannot be altered by simple distillation. This happensbecause the vapor it produces has proportionate constituents as theoriginal mixture when an azeotrope is boiled. Example azeotropes of theformulations include ethanol/water, ethanol/water/contrast agent,ethanol/water/surfactant, ethanol/water/contrast agent/surfactant,propanol/water, iso-propanol/water, butanol/water, acetic acid/water,acetic acid/water/ethanol, acetic acid/water/contrast agent, aceticacid/water/contrast agent/surfactant, acetic acid/water/ethanol/contrastagent, acetic acid/water/ethanol/contrast agent/surfactant, lacticacid/water, lactic acid/water/ethanol, lactic acid/water/contrast agent,lactic acid/water/contrast agent/surfactant, lacticacid/water/ethanol/contrast agent, lactic acid/water/ethanol/contrastagent/surfactant, ethyl lactate/water, ethyl lactate/ethanol, lacticacid/ethanol/water, ethyl lactate/water/ethanol, ethyl acetate/ethanol,ethyl nitrate/ethanol, isopropyl acetate/ethanol, and theircombinations.

In some embodiments, the formulation is in state of gases or vapors ofone or more ingredients. Example vapor or gas formulation includesoxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide,water, phenol, methanol, ethanol, absolute alcohol, isopropanol,propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid,lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methylacetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactateand their mixtures. The vapor formulation may include a surfactant. Thevapor formulation may include a therapeutic agent. The vapor formulationcan include a contrast agent, such as lipiodol, iodine. The vapor caninclude an azeotrope. The vapor can be one of binary, ternary, fourcomponent, or more than four component formulations. The elevatedtemperature of the vapor formulation can be in the range of 0-140° C.,preferable of 15-100° C., most preferable of 20-85° C. The pressure ofthe vapor infused is higher than body lumen pressure (1 ATM). Thepressure range of the vapor infused to the target tissue is from 1 to 12ATM, or 1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the formulation is in state of liquid of one ormore ingredients. Example liquid formulations include water, saline,hypertonic saline, phenol, methanol, ethanol, absolute alcohol,isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol,acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide,lipiodol, methyl acetate, ethyl acetate, ethyl nitrate, isopropylacetate, ethyl lactate, urea, surfactant, and others. The liquidformulation may include a therapeutic agent. The liquid formulation mayinclude a contrast agent. The liquid formulation may include anazeotrope. The liquid formulation can be one of binary, ternary, fourcomponent, or more than four component formulations. The desiredtemperature of the liquid formulation can be in the range of −40 to 140°C., preferable of −30 to 100° C., most preferable of −20 to 80° C. Thepressure of the liquid infused is higher than body lumen pressure (1ATM). The pressure range of the liquid infused to the target tissue isfrom 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM. Theliquid formulation can include a solution. The liquid formulation caninclude a suspension. The liquid formulation includes an emulsion.

In some embodiments, the method for treating a diseases involvesinserting a delivery catheter percutaneously into the diseased tissuesof a human body, infusing the formulation through the catheter to thetissues of the body, wherein the amount of the formulation and/or heator cool delivered is effective to injury or damage the tissues to have atherapeutic benefit (e.g., neuromodulation, lowering blood pressure,treating shortness of breath), and withdrawing the delivery catheterfrom the body. Heating or cooling can be used to enhance the effect byaccelerating reaction rates of the formulation and the tissues. Examplediseases include hypertension, diabetes, obesity, heart failure,end-stage renal disease, digestive disease, urological disease, cancers,tumors, pains, asthma, pulmonary arterial hypertension, and chronicobstructive pulmonary disease (COPD). Example body tissues includesrenal arteries, vascular lumen, nonvascular lumen, airway, sinus,esophagus, respiratory lumens, digestive lumens, cancers, tumors, pains,and urological lumens. Example formulations include gases, vapors,liquids, solutions, emulsion, and suspensions of one or moreingredients. If the formulation is a vapor of one or more ingredients,the heat can be generated by condensation of the vapors into liquids inthe tissue. If the formulation is a liquid or solutions, the cool orheat can be generated by the temperature of the formulation (i.e., aboveor below body temperature). The temperature of the liquid formulationcan be in the range of −40 to 140° C., preferable of −30 to 100° C.,most preferable of −20 to 80° C. The temperature of the formulations canbe at room temperature in one embodiment. The temperature of theformulations is in the range of −40 to −20° C. in some embodiments. Thetemperature of the formulations is in the range of 15 to 80° C. in someembodiments. The temperature of the formulations is at body temperaturein some embodiments. The temperature of the formulations is in the rangeof 50 to 80° C. in some embodiments. The temperature of the treatedtissue is lower than the desired temperature of the formulation andhigher than that of body temperature in some embodiments. Thetemperature of the treated tissue can be in the range of −40 to 100° C.,preferable of −30 to 80° C., most preferable of −20 to 80° C. Thetemperature of the treated tissue is in the range of −40 to −20° C. insome embodiments. The temperature of the treated tissue is in the rangeof 15 to 80° C. in some embodiments. The temperature of the treatedtissue is at body temperature in some embodiments. The temperature ofthe treated tissue is in the range of 50 to 80° C. in some embodiments.The pressure of the formulation infused is higher than body lumenpressure (1 ATM). The pressure range of the formulation infused to thetarget tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM. The delivery catheter is a needle or needle basedcatheter under imaged guide. For example, the imaged guide can beultrasound, X-ray, CT scan, scopes, or a combination thereof. Thedelivery catheter can be a balloon based catheter. For example, theballoon based catheter can have single or double balloons. The deliverycatheter can be an infusion catheter. In some embodiments, the catheteris a combination of balloon catheter and infusion catheter.

In some embodiments, the method for treating diseases includes insertingan irrigated thermal ablation catheter percutaneously into the bodylumen adjacent to nerves, infusing the formulation to the tissue of thebody lumen adjacent to the nerves; thermally ablating the tissue of thebody lumen adjacent to the nerves; infusing the formulation during,before, and/or after the thermal ablation, wherein the amount offormulation and/or energy delivered is effective to injury or damage thenerves to have a benefit, such as lower blood pressure and shortness ofbreath; and withdrawing the irrigated thermal ablation catheters fromthe body lumen. The irrigated thermal ablation catheters can be selectedfrom the group consisting of radiofrequency, cryoablation, microwave,laser, ultrasound, and high-intensity focused ultrasound irrigatedablation catheters. The energy can enhance the effect by acceleratingreaction rate of the formulation and the nerves. The diseases can beselected from the group consisting of hypertension, diabetes, obesity,heart failure, end-stage renal disease, digestive disease, urologicaldisease, asthma, pulmonary arterial hypertension, and chronicobstructive pulmonary disease (COPD). The body lumen can comprise renalarteries, vascular lumen, nonvascular lumen, airway, sinus, esophagus,respiratory lumens, digestive lumens, and/or urological lumens. Theformulations can be selected from the group consisting of gases, vapors,liquids, solutions, emulsion, and suspensions of one or moreingredients. If the formulation comprises vapors of one or moreingredients, the heat can be generated by condensation of the vaporsinto liquids in the tissue. If the formulation is liquids or solutions,the cool or heat can be generated by the temperature of the formulationabove or below body temperature. The temperature of the liquidformulation can be in the range of −40 to 140° C., preferable in therange of −30 to 100° C., most preferable in the range of −20 to 80° C.The temperature of the formulations is at room temperature in someembodiments. The temperature of the formulations is in the range of −40to −20° C. in some embodiments. The temperature of the formulations isin the range of 15 to 80° C. in some embodiments. The temperature of theformulations is at body temperature in some embodiments. The temperatureof the formulations is in the range of 50 to 80° C. in some embodiments.The temperature of the treated tissue adjacent to the nerves is lowerthan the desired temperature of the formulation and higher than that ofbody temperature in some embodiments. The temperature of the treatedtissue adjacent to the nerves can be in the range of −40 to 100° C.,preferable in the range of −30 to 80° C., most preferable in the rangeof −20 to 80° C. The temperature of the treated tissue adjacent to thenerves is in the range of −40 to −20° C. in some embodiments. Thetemperature of the treated tissue adjacent to the nerves is in the rangeof 15 to 80° C. in some embodiments. The temperature of the treatedtissue adjacent to the nerves is at body temperature in someembodiments. The temperature of the treated tissue adjacent to thenerves is in the range of 50 to 80° C. in some embodiments. The pressureof the formulation infused is higher than body lumen pressure (1 ATM).The pressure range of the formulation infused to the target tissue isfrom 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the combination of non-irrigated thermal ablationcatheter and the formulation delivery catheter can be used alternativelyor simultaneously for treatment of a disease. The method for treatingdiseases can comprise inserting a non-irrigated thermal ablationcatheter or/and a formulation delivery catheter percutaneous into thebody lumen adjacent to nerves; infusing the formulation to the tissue ofthe body lumen adjacent to the nerves; thermally ablating the tissue ofthe body lumen adjacent to the nerves; infusing the formulation during,before, and/or after the thermal ablation, wherein amount of theformulation and/or energy delivered is effective to injury or damage thenerves to have a benefit, such as lower blood pressure and shortness ofbreath; and withdrawing the non-irrigated thermal ablation catheteror/and the formulation delivery catheter from the body lumen. Thenon-irrigated thermal ablation catheters can be selected from the groupconsisting of radiofrequency, cryoablation, microwave, laser,ultrasound, and high-intensity focused ultrasound non-irrigated ablationcatheters. The formulation delivery catheter can be a needle basedcatheter. The formulation delivery catheter can also a balloon basedcatheter. The balloon based catheters can have single or doubleballoons. The formulation delivery catheters can be an infusioncatheter. The energy can enhance the effect by accelerating reactionrate of the formulation and the nerves. The diseases can be selectedfrom the group consisting of hypertension, diabetes, obesity, heartfailure, end-stage renal disease, digestive disease, urological disease,asthma, pulmonary arterial hypertension, and chronic obstructivepulmonary disease (COPD). The body lumen can be selected from the groupconsisting of renal arteries, vascular lumen, nonvascular lumen, airway,sinus, esophagus, respiratory lumens, digestive lumens, and urologicallumens. The formulations be selected from the group consisting of gases,vapors, liquids, solutions, emulsion, and suspensions of one or moreingredients. If the formulation is vapors of one or more ingredients,the heat can be generated by condensation of the vapors into liquids inthe tissue. If the formulation is liquids or solutions, the cool or heatcan be generated by the temperature of the formulation above or belowbody temperature. The temperature of the liquid formulation can be inthe range of −40 to 140° C., preferable in the range of −30 to 100° C.,most preferable in the range of −20 to 80° C. The temperature of theformulations is at room temperature in some embodiments. The temperatureof the formulations is in the range of −40 to −20° C. in someembodiments. The temperature of the formulations is in the range of 15to 80° C. in some embodiments. The temperature of the formulations is atbody temperature in some embodiments. The temperature of theformulations is in the range of 50 to 80° C. in some embodiments. Thetemperature of the treated tissue adjacent to the nerves is lower thanthe desired temperature of the formulation and higher than that of bodytemperature in some embodiments. The temperature of the treated tissueadjacent to the nerves can be in the range of −40 to 100° C., preferablein the range of −30 to 80° C., most preferable in the range of −20 to80° C. The temperature of the treated tissue adjacent to the nerves isin the range of −40 to −20° C. in some embodiments. The temperature ofthe treated tissue adjacent to the nerves is in the range of 15 to 80°C. in some embodiments. The temperature of the treated tissue adjacentto the nerves is at body temperature in some embodiments. Thetemperature of the treated tissue adjacent to the nerves is in the rangeof 50 to 80° C. in some embodiments. The pressure of the formulationinfused is higher than body lumen pressure (1 ATM). The pressure rangeof the formulation infused to the target tissue is from 1 to 12 ATM, or1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present invention as claimed.

DESCRIPTION OF DRAWINGS

FIG. 1 is a perspective view of an exemplary embodiment of a doubleballoon delivery catheter embodiment.

FIG. 2A is an embodiment of formulation infusion to the airway with thesingle balloon delivery catheter.

FIG. 2B is an embodiment of formulation infusion to the airway with thedouble balloon delivery catheter.

FIG. 2C is an embodiment of formulation infusion to the renal arterywith the double balloon delivery catheter.

FIG. 3 is an embodiment of a partial cross-sectional view of the doubleballoon delivery catheter in a body lumen.

FIG. 4 is an embodiment of formulation infusion to pulmonary artery withthe double balloon delivery catheters.

DETAILED DESCRIPTION

Disclosed are embodiments directed to the treatment of a disease bydelivering an effective amount of a formulation to target tissues, suchas diseased tissue. The term “diseased tissue” includes any tissue thatcontributes to a disease. For example, the disease can be one ofhypertension, diabetes, obesity, heart failure, end-stage renal disease,digestive disease, urological disease, cancer, tumor, pains, asthma,pulmonary arterial hypertension, and chronic obstructive pulmonarydisease (COPD). Example cancers include adrenal, bladder, cervical,colon, esophageal, gallbladder, kidney, liver, lung, ovarian,pancreatic, prostatic, rectal, stomach, and uterine cancers. Theformulation comprise one or more gases, vapors, liquids, solutions,emulsions, and suspensions of one or more ingredients. The methods caninvolve delivering the formulations at desired temperature to tissues ofhuman body. Example tissues include renal arteries, vascular lumen,nonvascular lumen, airway, sinus, esophagus, respiratory lumens,digestive lumens, cancers, tumors, and urological lumens. Thetemperature may enhance safety and efficacy of the formulations for thetreatments. The temperature can be in the range of −40 to 140° C.,preferable of −30 to 100° C., most preferable of −20 to 80° C. Thetemperature of the treated tissue can be different from the temperatureof the formulation. The temperature of the treated tissue can be in therange of −40 to 100° C., preferable of −30 to 80° C. The pressure of theformulation infused is higher than body lumen pressure (1 ATM). Thepressure range of the formulation infused to the target tissue is from 1to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM. The amountof the formulation and energy delivered is preferably effective toinjure or damage or eliminate diseased tissues to have a therapeuticbenefit, such as lowering blood pressure, shrinking tumors, relievingpains, relieving symptoms of asthma, pulmonary arterial hypertension,and treating COPD. Energy or heat can in some embodiments enhance theeffect by accelerating reaction rates of the formulation and thetissues.

Disclosed are embodiments directed to the treatment of a disease bydelivering of an effective amount of energy or/and formulations totarget nerve tissue. For example, the disease can be selected from thegroup consisting of hypertension, diabetes, obesity, heart failure,end-stage renal disease, digestive disease, urological disease, asthma,pulmonary arterial hypertension, and chronic obstructive pulmonarydisease (COPD). The energy can be radiofrequency, cryoablation,microwave, laser, ultrasound, and/or high-intensity focused ultrasoundenergies. The formulations can be gases, vapors, liquids, solutions,emulsions, and/or suspensions of one or more ingredients. The methodscan involve the combination of thermal and chemical ablation, theirformulations, and methods for treatments of hypertension, diabetes,obesity, heart failure, end-stage renal disease, digestive disease,urological disease, asthma, pulmonary arterial hypertension and chronicobstructive pulmonary disease (COPD) by thermal and chemical ablationsto nerves of human body at various temperatures. The thermal energy mayenhance safety and efficacy of the chemical ablation for the treatments.The chemical ablation may improve safety and efficacy of thermalablation for the treatments by lowing ablation temperature and/or time.The temperature can be in the range of −40 to 140° C., preferable in therange of −30 to 100° C., most preferable in the range of −30 to 80° C.The pressure of the formulation infused is higher than body lumenpressure (1 ATM). The pressure range of the formulation infused to thetarget tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM. The formulation can be one of binary, ternary,four component, or more than four component formulations. The deliverysystem can be a percutaneous less invasive delivery catheter. Thedisclosed methods can provide a combination of thermal energy andformulation comprising one or more ingredients that enhance absorptionand penetration into the nerves of body lumens.

In some embodiments, safety and efficacy of the radiofrequency ablationis improves by increasing ablation size, while minimizing risks forcomplications that can arise during the heating. Examples of suchcomplications include thrombus formation, steam pops, bubbling, charringon the lesion, restenosis, fibrosis in the media and the adventitia, andothers related to catheter manipulation (i.e., perforations). Spotthermal ablation (RF ablation) is not uniform and it does not reach tothe nerves in adventitia. Partially spot RF ablation leads to lowefficacy (low blood pressure drops). The methods include the electrodesize (passive cooling via the blood flow) and cooling the electrodethrough active fluids cooling either internally (closed-loop) orexternally (open-loop). Cooling electrodes increases energy deliveryinto the nerve tissue. In one embodiment of externally cooling(open-loop), the chemical formulation can replace the active coolingfluids. The disclosed formulations can be used not only for coolingelectrodes, but also used for chemical ablation. The formulations can insome embodiments diffuse and permeate into the nerve tissue uniformly,and they can ablate the nerves in adventitia uniformly in the bodylumen. Therefore, the chemical ablation formulation can be deliveredduring, before, and/or after the thermal ablations. Examples of thermalablations include radiofrequency, cryoablation, microwave, laser,ultrasound, and high-intensity focused ultrasound. Therefore, themethods can improve safety and efficacy of the treatments.

The formulation can be one of binary, ternary, four component, or morethan four component formulations. The delivery system can be apercutaneous, less invasive delivery method. Also provided is aformulation comprising one or more ingredients that enhance absorptionand penetration into tissues of the body lumens.

In some embodiments, the ingredient of the formulation is chosen fromwater, saline, hypertonic saline, phenol, methanol, ethanol, absolutealcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol,glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide,ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropylacetate, ethyl lactate, urea, lipiodol, surfactant, derivatives andcombinations thereof.

In some embodiments, the ingredient of the formulation is a gas. Examplegases include oxygen, nitrogen, helium, argon, air, carbon dioxide,nitric oxide, vapors of organic and inorganic compounds, water, phenol,methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol,isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyliodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate,ethyl nitrate, isopropyl acetate, ethyl lactate, and their mixtures.

In some embodiments, the ingredient in the formulation is a surfactant.Example surfactants include PEG laurate, Tween 20, Tween 40, Tween 60,Tween 80, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, benzalkoniumchloride, benzethonium chloride, docecyl trimethyl ammonium bromide,sodium ricinoleate, dioctyl sodium sulfosuccinate, sodium laurylsulfate, sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride,and dialkylesters of sodium sulfonsuccinic acid, organic acid, salts ofany organic acid and organic amine, polyglycidol, glycerol,multiglycerols, galactitol, di(ethylene glycol), tri(ethylene glycol),tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol)oligomers, di(propylene glycol), tri(propylene glycol), tetra(propyleneglycol, and penta(propylene glycol), poly(propylene glycol) oligomers, ablock copolymer of polyethylene glycol and polypropylene glycol,Pluronic, Pluronic 85, and derivatives and combinations thereof. Thecontent of the surfactant in the formulation can be in the range of 0.1to 80% by weight, preferably 0.5 to 50% by weight, most preferably 1 to15% by weight.

In some embodiments, at least one oil, fatty acid, and/or a lipid is inthe formulation. For example, the formulation can comprise soybean oil,vegetable oil, flower oil, animal oil, marine oil, butterfat, coconutoil, palm oil, olive oil, peanut oil, fish oil, butanoic acid, hexanoicacid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid,hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoicacid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid,docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylicacid, capric acid, lauric acid, myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucicacid, lignoceric acid, natural or synthetic phospholipids, mono-, di-,or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidicacid, phosphatidylcholine, alpha tocoferol, phosphatidylethanolamine,sphingomyelin, phosphatidylserine, phosphatidylinositol,dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,phosphatidylethanolamines phosphatidylglycerols, sphingolipids,prostaglandins, gangliosides, neobee, niosomes, and derivatives thereof.

In some embodiments, the formulation includes one or more therapeuticagents or drugs for nerve denervation. The therapeutic agent can be oneof sodium channel blockers, tetrodotoxin, saxitoxin, decarbamoylsaxitoxin, vanilloids, neosaxitoxin, lidocaine, conotoxins, cardiacglycosides, digoxin, glutamate, staurosporine, amlodipine, verapamil,cymarin, digitoxin, proscillaridin, quabain, veratridine, domoic acid,oleandrin, carbamazepine, aflatoxin, guanethidine, and guanethidinesulfate. In another embodiment, the formulation includes one of thecontrast agents for imaging nerve denervation. The contrast agent canincludes iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynoliodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide,ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and theirderivatives. The content of the contrast agent in the formulation can bein the range of 2 to 25% by weight, preferable 5 to 15% by weight.

In some embodiments, the formulation includes an azeotrope. An azeotropeis a mixture of two or more ingredients in such a way that itscomponents can not altered by simple distillation. This happens becausethe vapor it produces has proportionate constituents as the originalmixture when an azeotrope is boiled. The azeotropes or the formulationscan include ethanol/water, ethanol/water/contrast agent,ethanol/water/surfactant, ethanol/water/contrast agent/surfactant,propanol/water, iso-propanol/water, butanol/water, acetic acid/water,acetic acid/water/ethanol, acetic acid/water/contrast agent, aceticacid/water/contrast agent/surfactant, acetic acid/water/ethanol/contrastagent, acetic acid/water/ethanol/contrast agent/surfactant, lacticacid/water, lactic acid/water/ethanol, lactic acid/water/contrast agent,lactic acid/water/contrast agent/surfactant, lacticacid/water/ethanol/contrast agent, lactic acid/water/ethanol/contrastagent/surfactant, ethyl lactate/water, ethyl lactate/ethanol, lacticacid/ethanol/water, ethyl lactate/water/ethanol, ethyl acetate/ethanol,ethyl nitrate/ethanol, and isopropyl acetate/ethanol.

In some embodiments, the formulation is in state of gases or vapors ofone or more ingredients. The gas or vapor formulation can compriseoxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, andvapors of organic and inorganic compounds. The vapors of the organic andinorganic compounds can include water, phenol, methanol, ethanol,absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethyleneglycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyliodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate,isopropyl acetate, ethyl lactate and their mixtures.

The vapor formulation may include a surfactant. The vapor formulationmay include a therapeutic agent. The vapor formulation may include acontrast agent, such as lipiodol and iodine. The vapor may include anazeotrope. The vapor can be one of binary, ternary, four component, ormore than four component formulations. The desired temperature of thevapor formulation can be in the range of 0 to 140° C., preferable of 15to 100° C., most preferable of 30 to 80° C. The pressure of the vaporinfused is higher than body lumen pressure (1 ATM). The pressure rangeof the vapor infused to the target tissue is from 1 to 12 ATM, or 1 to 8ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the formulation is in state of liquid of one ormore ingredients. The liquid formulation can include water, saline,hypertonic saline, phenol, methanol, ethanol, absolute alcohol,isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol,acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide,lipiodol, methyl acetate, ethyl acetate, ethyl nitrate, isopropylacetate, ethyl lactate, urea, surfactant, and others. The liquidformulation may include a therapeutic agent. The liquid formulation mayinclude a contrast agent. The liquid formulation may include anazeotrope. The liquid formulation can be one of binary, ternary, fourcomponent, or more than four component formulations. The liquidformulation may be a solution. The liquid formulation may be anemulsion. The liquid formulation may be a suspension. The temperature ofthe liquid formulation can be in the range of −40 to 140° C., preferablyin the range of −30 to 100° C., most preferably in the range of −30 to80° C. The temperature of the formulations is at room temperature insome embodiments. The temperature of the formulations is in the range of−40 to −20° C. in some embodiments. The temperature of the formulationsis in the range of 15 to 80° C. in some embodiments. The temperature ofthe formulations is at body temperature in some embodiments. Thetemperature of the formulations is in the range of 50 to 80° C. in someembodiments. The pressure of the liquid infused is higher than bodylumen pressure (1 ATM). The pressure range of the liquid infused to thetarget tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM.

In some embodiments, the method for treating a diseases includesinserting a delivery catheter percutaneously into the body; infusing theformulation through the catheter to the diseased tissue of the body,wherein amount of the formulation and/or heat or cool delivered iseffective to injury or damage the tissues to have a therapeutic benefit(e.g., lower blood pressure and shortness of breath), and withdrawingthe delivery catheter from the body. Heat or cool can enhance the effectby accelerating reaction rate of the formulation and the tissues.Example diseases that can be treated include hypertension, diabetes,obesity, heart failure, end-stage renal disease, digestive disease,urological disease, cancers, tumors, pains (chronic and/or acute),asthma, pulmonary arterial hypertension, and chronic obstructivepulmonary disease (COPD). Cancers include adrenal, bladder, cervical,colon, esophageal, gallbladder, kidney, liver, lung, ovarian,pancreatic, prostatic, rectal, stomach, and uterine cancers. Bodytissues include renal arteries, vascular lumen, nonvascular lumen,airway, sinus, esophagus, respiratory lumens, digestive lumens, cancers,tumors, and urological lumens. The formulation can be a gas, vapor,liquid, solution, emulsion, or suspension comprising one or moreingredients. If the formulation is a vapor of one or more ingredients,the heat can be generated by condensation of the vapors into liquids inthe tissue. If the formulation is a liquid or solution, the cool or heatcan be generated by the temperature of the formulation, i.e., below orabove body temperature. The temperature of the liquid formulation can bein the range of −40 to 140° C., preferably in the range of −30 to 100°C., most preferably in the range of −30 to 80° C. The temperature of thetreated tissue can be different from the temperature of the formulationand lower or higher than that of body temperature in some embodiments.The temperature of the treated tissue can be in the range of 15-100° C.,preferably in the range of 20-90° C., most preferably in the range of36-80° C. The temperature of the treated tissue can be in the range of−40 to −20° C. in some embodiments. The pressure of the formulationinfused is higher than body lumen pressure (1 ATM). The pressure rangeof the formulation infused to the target tissue is from 1 to 12 ATM, or1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM. The delivery cathetercan be a needle or a needle based catheter under imaged guide. Theimaged guide can be one of ultrasound, X-ray, CT-scan, and scopes. Thedelivery catheter can also be a balloon based catheter. Balloon basedcatheters can have at least one or two balloons. The delivery cathetercan be an infusion catheter. The catheter can be a combination ofballoon catheter and an infusion catheter.

In some embodiments, the method for treating disease includes insertinga delivery catheter percutaneously into the body lumen adjacent tonerves; delivering the energy or/and the formulation above described ata desired temperature to the tissue of the body lumen adjacent to thenerves, wherein the amount of formulation and/or energy delivered iseffective to injury or damage the nerves to have a benefit, such aslower blood pressure; and withdrawing the delivery catheters from thebody lumen. Example diseases that can be treated include hypertension,diabetes, obesity, heart failure, end-stage renal disease, digestivedisease, urological disease, cancers, tumors, pains (chronic and/oracute), asthma, pulmonary arterial hypertension and chronic obstructivepulmonary disease (COPD). Cancers include adrenal, bladder, cervical,colon, esophageal, gallbladder, kidney, liver, lung, ovarian,pancreatic, prostatic, rectal, stomach, and uterine cancers. Bodytissues include renal arteries, vascular lumen, nonvascular lumen,pulmonary artery, airway, sinus, esophagus, respiratory lumens,digestive lumens, cancers, tumors, and urological lumens. The energy canin some embodiments enhance the effect by accelerating reaction rate ofthe formulation and the nerves. The energy can be one of radiofrequency,cryoablation, microwave, laser, ultrasound, and high-intensity focusedultrasound energies. The energy delivery catheter can therefore be oneof radiofrequency, cryoablation, microwave, laser, ultrasound, andhigh-intensity focused ultrasound catheters. Example formulationsinclude gases, vapors, liquids, solutions, emulsion, and suspensions ofone or more ingredients. If the formulation is vapors of one or moreingredients, the heat can be generated by condensation of the vaporsinto liquids in the tissue. If the formulation is liquids or solutions,the heat can be transferred by the high temperature formulations abovebody temperature. The desired temperature of the formulation can be inthe range of −40 to 140° C., preferable in the range of −30 to 100° C.,most preferable in the range of −20 to 80° C. The temperature of thetreated tissue adjacent to the nerves can be lower than the desiredtemperature of the formulation and higher than that of the bodytemperature. The temperature of the treated tissue adjacent to thenerves can be in the range of −40 to 100° C., preferable in the range of−30 to 90° C., most preferable in the range of −20 to 80° C. Thepressure of the formulation infused is higher than body lumen pressure(1 ATM). The pressure range of the formulation infused to the targettissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM, preferred 1 to3 ATM.

In some embodiments, the formulation is a mixture of ethanol and water.The ethanol content of ethanol can be in the range of 10-100% by weight.The formulation can be delivered to the tissues of body lumen as vaporsor liquid at desired temperature. The desired temperature of the vaporor liquid formulation can be in the range of −40 to 150° C., preferablyin the range of −30 to 100° C., most preferably in the range of −20 to80° C. The temperature of the tissue can be in the range of −40 to 90°C., preferably in the range of −30 to 80° C. The ethanol/waterformulation can be a positive azeotrope. The azeotrope can be 95.63%ethanol and 4.37% water (by weight). Ethanol boils at 78.4° C., waterboils at 100° C., but the azeotrope boils at 78.2° C., which is lowerthan either of its constituents. 78.2° C. is the minimum temperature atwhich any ethanol/water solution can boil at atmospheric pressure. Thepressure of the mixture of ethanol and water infused is higher than bodylumen pressure (1 ATM). The pressure range of the formulation infused tothe target tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM.

In some embodiments, the delivery catheter is a combination catheter ofradiofrequency and infusion catheters. The radiofrequency catheters canbe modified by reducing the electrode size (resulting in passive coolingvia the blood flow) and/or cooling the electrode through active fluids,cooling either internally (closed-loop) or externally (open-loop).Cooling electrodes increases energy delivery into the nerve tissue. Insome embodiments of externally cooling (open-loop), the chemicalformulation can replace the active cooling fluids. The disclosedformulation can in some embodiments be used not only for coolingelectrodes, but also for chemical ablation. The formulations can diffuseand permeate into the nerve tissue uniformly, and they can ablate thenerves in adventitia uniformly in the body lumen. Therefore, thechemical ablation formulation can be delivered during, before, and/orafter the thermal ablations. The thermal ablations can involveradiofrequency, cryoablation, microwave, laser, ultrasound, and/orhigh-intensity focused ultrasound. Therefore, the methods can improvesafety and efficacy of the treatments.

In some embodiments, the delivery catheter comprises infusion lumen,energy delivery lumen, guide wire lumen, inflation lumen, energydelivery port, formulation infusion port, and balloon inflation ports atthe proximal end, energy releasing element, formulation releasing exit,and single or double balloons at distal end. The energy delivery elementcan be one of radiofrequency, cryoablation, microwave, laser,ultrasound, and high-intensity focused ultrasound. The energy generatorcan be connected to the energy delivery port. The energy generator canbe one of radiofrequency, cryoablation, microwave, laser, ultrasound,and high-intensity focused ultrasound energy generators. The ballooninflation port can be connected to inflation device. The formulationresource can be connected to the formulation infusion port at theproximal end of the delivery catheters.

In some embodiments, the formulation is a mixture of vapors comprisingwater, ethanol and oxygen. In another embodiment, the formulation is amixture of vapors comprising water, ethanol and air. In someembodiments, the formulation is a mixture of vapors comprising water,ethanol, oxygen and nitrogen. These formulations with oxygen or air areespecially useful for treatments of asthma and COPD.

In some embodiments, the formulation is a mixture of vapors comprisingwater, ethanol and iodine, wherein iodine vapor has effective amount toimage the mixture of vapors in the wall of the body lumen. In someembodiments, the formulation is a mixture of liquids comprising water,ethanol and a surfactant. In some embodiments, the formulation is amixture of liquids comprising water, ethanol and a contrast agent,wherein the contrast agent has effective amount to track the mixture inthe wall of the body lumen by X-ray. The contrast agent can be one ormore of iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine,iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol,ioxilan, iotrolan, iodixanol, ioxaglate, and their derivatives. Thecontent of the contrast agent in the formulation can be in the range of2 to 20% by weight, preferably 5 to 15% by weight.

In some embodiments, the formulation is a mixture of acetic acid andwater. The acetic acid content of the formulation can be in the range of1-100% by weight, preferably 10-75% by weight, most preferable 20-50% byweight. The formulation can be delivered to the tissues of body lumen asvapors or liquid at desired temperature. The desired temperature of thevapor or liquid formulation can be in the range of −40 to 100° C.,preferably in the range of −30 to 100° C., most preferably in the rangeof −30 to 80° C. The temperature of the tissue can be in the range of−30 to 80° C., preferably in the range 60 to 80° C. or −40 to −20° C.The temperature of the tissue can be in the range of −40 to 0° C.,preferably in the range −30 to −20° C. The pressure of the mixture ofacetic acid and water infused is higher than body lumen pressure (1ATM). The pressure range of the formulation infused to the target tissueis from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.The acetic acid content in the formulation can be from 2% to 75% (byweight), preferably from 10% to 60% (by weight).

In some embodiments, the formulation is a mixture of liquids comprisingwater, acetic acid and a contrast agent, such as sodium iodide andlipiodol, wherein the contrast agent has effective amount to image themixture of vapors in the wall of the body lumen. The acetic acid contentof the formulation can be in the range of 1-100% by weight, preferably10-75% by weight, most preferably 30-60% by weight. In anotherembodiment, the formulation is a mixture of liquids comprising water,acetic acid and a surfactant. The acetic acid content of the formulationcan be in the range of 1-100% by weight, preferably 10-75% by weight,most preferably 30-60% by weight. In another embodiment, the formulationis a mixture of liquids comprising water, acetic acid and a contrastagent, wherein the contrast agent has effective amount to track themixture in the wall of the body lumen by X-ray. The contrast agent canbe one of iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynoliodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide,ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and theirderivatives. The content of the contrast agent in the formulation can bein the range of 2 to 20% by weight, preferably 5 to 15% by weight.

In some embodiments, the formulation is a mixture of liquids comprisingethanol and lipiodol (LIPIODOL ULTRA-FLUIDE), wherein the lipiodol haseffective amount to image the mixture of vapors in the wall of the bodylumen and also to injury the target nerve tissue. The lipiodol contentof the formulation can be in the range of 10-80% by weight, preferably15-75% by weight, most preferably 20-50% by weight. In anotherembodiment, the formulation is a mixture of liquids comprising water andlipiodol. The lipiodol content of the formulation can be in the range of10-80% by weight, preferably 15-75% by weight, most preferably 20-50% byweight. In another embodiment, the formulation is a mixture of liquidscomprising acetic acid and lipiodol. The content of the lipiodol in theformulation can be in the range of 10-80% by weight, preferably 15-75%by weight, most preferably 20-50% by weight.

In some embodiments, the formulation is a solution of phenol, water, andamount of a contrast agent, such as iodine, sodium iodide, lipiodol andiopromide. The phenol content can be in the range of 2-20% by weight,preferably 5-16% by weight. The formulation can be delivered to thetissues of body lumen as a solution at desired temperature. The desiredtemperature of the liquid formulation can be in the range of 0-100° C.,preferably 20-95° C., most preferably 50-90° C. The temperature of thetissue can be in the range of 36-80° C., preferably 60-80° C. The phenolcan be an effective agent for ablation. The pressure of the solutioninfused is higher than body lumen pressure (1 ATM). The pressure rangeof the solution infused to the target tissue is from 1 to 12 ATM, or 1to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the formulation is a solution of ethylene glycol,water, and a small amount of a contrast agent, such as iodine andiopromide. The ethylene glycol content can be in the range of 2-90% byweight, preferably 15-75% by weight. The desired temperature of theliquid formulation can be in the range of 20-150° C., preferably of40-120° C., most preferably of 60-90° C. The pressure of the solutioninfused is higher than body lumen pressure (1 ATM). The pressure rangeof the solution infused to the target tissue is from 1 to 12 ATM, or 1to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the formulation is a solution of glycerol, water,and a small amount of a contrast agent, such as iodine and iopromide.The glycerol content can be in the range of 2-90% by weight, preferably15-75% by weight. The desired temperature of the liquid formulation canbe in the range of 20-150° C., preferably 40-120° C., most preferably60-90° C. The pressure of the solution infused is higher than body lumenpressure (1 ATM). The pressure range of the solution infused to thetarget tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM.

In some embodiments, the formulation is a mixture of propanol and water.The propanol content of ethanol can be in the range of 10-99% by weight.The formulation can be delivered to the nerves of body lumen as vaporsor liquid at desired temperature. The desired temperature of the vaporor liquid formulation can be in the range of 20-100° C., preferably40-95° C., most preferably 60-90° C. The temperature of the nerve tissuecan be in the range of 36-80° C., preferably 60-80° C. Thepropanol/water formulation can be an azeotrope. The azeotrope can be71.7% propanol and 28.3% water (by weight). Propanol boils at 97.2° C.,water boils at 100° C., but the azeotrope boils at 87.7° C., which islower than either of its constituents. The pressure of the solutioninfused is higher than body lumen pressure (1 ATM). The pressure rangeof the solution infused to the target tissue is from 1 to 12 ATM, or 1to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the formulation is a mixture of isopropanol andwater. The isopropanol content can be in the range of 10-99% by weight.The formulation can be delivered to the nerves of body lumen as vaporsor liquid at desired temperature. The desired temperature of the vaporor liquid formulation can be in the range of 20-100° C., preferably40-95° C., most preferably 60-90° C. The temperature of the nerve tissuecan be in the range of 20-80° C., preferably 60-80° C. Theisopropanol/water formulation can be an azeotrope. The azeotrope can be87.9% propanol and 12.1% water (by weight). Isopropanol boils at 82.5°C., water boils at 100° C., but the azeotrope boils at 80.4° C., whichis lower than either of its constituents. The pressure of the solutioninfused is higher than body lumen pressure (1 ATM). The pressure rangeof the solution infused to the target tissue is from 1 to 12 ATM, or 1to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the formulation is a mixture of ethanol and ethylacetate. The content of ethyl acetate can be in the range of 10-99% byweight. The formulation can be delivered to the tissues of human body asvapors or liquid at desired temperature. The desired temperature of thevapor or liquid formulation can be in the range of 20-100° C.,preferably 40-95° C., most preferably 60-90° C. The temperature of thetissue can be in the range of 36-80° C., preferably 60-80° C. The ethylacetate/ethanol formulation can be an azeotrope. The azeotrope can be69.7% ethyl acetate and 30.3% ethanol (by weight). Ethyl acetate boilsat 77.1° C., ethanol boils at 78.4° C., but the azeotrope boils at 71.8°C., which is lower than either of its constituents. The pressure of thesolution infused is higher than body lumen pressure (1 ATM). Thepressure range of the solution infused to the target tissue is from 1 to12 ATM, or 1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the formulation is a mixture of ethanol and ethyliodide. The content of ethyl iodide can be in the range of 10-99% byweight. The formulation can be delivered to the nerves of body lumen asvapors or liquid at desired temperature. The desired temperature of thevapor or liquid formulation can be in the range of 20-100° C.,preferably 40-95° C., most preferably 60-90° C. The temperature of thetissue can be in the range of 36-80° C., preferably 60-80° C. The ethyliodide/ethanol formulation can be an azeotrope. The azeotrope can be 87%ethyl iodide and 13% ethanol (by weight). Ethyl iodide boils at 72.3°C., ethanol boils at 78.4° C., but the azeotrope boils at 63° C., whichis lower than either of its constituents. The pressure of the solutioninfused is higher than body lumen pressure (1 ATM). The pressure rangeof the solution infused to the target tissue is from 1 to 12 ATM, or 1to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the formulation is a mixture of water, ethanol, andethyl acetate. The content of ethanol can be in the range of 2-99% byweight. The content of ethyl acetate can be in the range of 2-85% byweight. The formulation can be delivered to the tissues of human body asvapors or liquid at desired temperature. The desired temperature of thevapor or liquid formulation can be in the range of 20-100° C.,preferably 40-95° C., most preferably 60-90° C. The temperature of thetissue can be in the range of 36-80° C., preferably 60-80° C. The ethylacetate/ethanol formulation can be an azeotrope. The azeotrope can be amixture of 7.8% water, 83.2% ethyl acetate, and 9.0% ethanol by weight.Ethyl acetate boils at 77.1° C., ethanol boils at 78.4° C. and waterboils at 100° C., but the azeotrope boils at 70.3° C., which is lowerthan any of its constituents. The pressure of the solution infused ishigher than body lumen pressure (1 ATM). The pressure range of thesolution infused to the target tissue is from 1 to 12 ATM, or 1 to 8 ATMor 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, a delivery catheter is used to infuse theformulation to tissues of a human body. The delivery catheter can be aneedle or needle-based catheter, e.g., under guidance of ultrasoundimaging. The delivery catheter can be a balloon based catheter. Theballoon based catheters can have at least one or two balloons, e.g.,comprise single or double balloons. The delivery catheter can be aninfusion catheter. The combination of balloon catheter and infusioncatheter can be used as well in the procedure.

Referring now to the figures, FIG. 1 shows a delivery catheter 10 havingan elongated shaft 11 with at least one inner lumen, a distal end 13,and a proximal end 14. At the distal end 13 are proximal 20 and distal21 lumen-conforming balloons. In any configuration, the tubing of thecatheter shaft 11 may be extruded from plastic materials, e.g.thermoplastics, polyimides, polyetherimides, polyethylenes,polyurethanes, polyesters, polyamide, Pebax, nylon, fluorinatedpolyurethane, polyether ether ketone, polysulfone, or the like. Thecatheter shaft 11 may be extruded or formed having a variety of lumencross-sections, including circular or elliptic lumens. Further, as shownin FIG. 1 , the catheter 10 may be equipped with a distal ballooninflation port 40 for the inflation of the distal balloon 21 and aproximal balloon inflation port 41 for inflation of the proximal balloon20, rendering the proximal 20 and distal 21 balloons separatelyinflatable. Lumen-conforming balloons are balloons that can be inflatedat a pressure less than that to deform the lumen wall. The balloonmaterial is selected to be flexible and usable at high temperature, suchthat the balloon, when inflated, is compliant. In some embodiments, theballoon material is one of polyamides, nylons, Pebax, polyesters,polyethylene teraphthalate, and their copolymers. The diameter of theballoons can range from about 2 millimeters to about 30 millimeters,dependent on the diameter of the treatment site. In some embodiments,the diameter of each balloon is about 2 millimeters (“mm”).Alternatively, the diameter of each balloon can be about 3 millimeters,or alternatively about 4 millimeters, or alternatively about 5millimeters, or alternatively about 6 millimeters, or alternativelyabout 7 millimeters, or alternatively about 8 millimeters, oralternatively about 9 millimeters, or alternatively about 10millimeters, or alternatively about 12 millimeters, or alternativelyabout 15 millimeters, or alternatively about 20 millimeters, oralternatively about 25 millimeters, or alternatively about 30millimeters.

In some embodiments, the catheter is electrode free. In particular, thecatheter can be free of any sources of ablative energy, such asradiofrequency, ultrasound, microwave energy.

In some embodiments, at least one marker band 22 b is located proximallyto the proximal balloon 20 and at least one marker band 23 a is locateddistally to the distal balloon 21. The balloon catheter may be a rapidexchange or over-the-wire catheter and made of any suitablebiocompatible material. The material of balloon 20 and 21 can be made ofone of polyesters, polyamides, nylon 12, nylon 11, polyamide 12, blockcopolymers of polyether and polyamide, Pebax, polyurethanes, and blockcopolymers of polyether and polyester. The diameter of balloon 21 can beequal or less than that of balloon 20.

FIGS. 2A and 2B are schematic views of a balloon delivery catheter 198positioned within a left main bronchus for treatments of asthma andCOPD. The delivery catheter 198 of FIGS. 2A and 2B can treat airwaysthat are distal to the main bronchi 21, 22. For example, the deliverycatheter 198 can be positioned in higher generation airways (e.g.,airway generations >2) to affect remote distal portions of the bronchialtree 27. The delivery system 198 can be navigated through tortuousairways to perform a wide range of different procedures, such as, forexample, denervation of a portion of a lobe, an entire lobe, multiplelobes, or one lung or both lungs. In some embodiments, the lobar bronchiare treated to denervate lung lobes. For example, one or more treatmentsites along a lobar bronchus may be targeted to denervate an entire lobeconnected to that lobar bronchus. Left lobar bronchi can be treated toaffect the left superior lobe and/or the left inferior lobe. Right lobarbronchi can be treated to affect the right superior lobe, the rightmiddle lobe, and/or the right inferior lobe. Lobes can be treatedconcurrently or sequentially. In some embodiments, a physician can treatone lobe. Based on the effectiveness of the treatment, the physician canconcurrently or sequentially treat additional lobe(s). In this manner,different isolated regions of the bronchial tree can be treated.

The delivery catheter 198 can also be used in segmental or subsegmentalbronchi. Each segmental bronchus may be treated by delivering theformulation to a single treatment site along each segmental bronchus.For example, the formulation can be delivered to each segmental bronchusof the right lung. In some procedures, one or two applications of theformulation can treat most of or substantially the entire right lung. Insome procedures, most or substantially all of both lungs are treatedusing less than two to six different applications. Depending on theanatomical structure of the bronchial tree, segmental bronchi can oftenbe denervated using one or two applications.

The delivery catheter 198 can affect nerve tissue while maintainingfunction of other tissue or anatomical features, such as the mucousglands, cilia, smooth muscle, body lumens (e.g., blood vessels), and thelike. Nerve tissue includes nerve cells, nerve fibers, dendrites, andsupporting tissue, such as neuroglia. Nerve cells transmit electricalimpulses, and nerve fibers are prolonged axons that conduct theimpulses. The electrical impulses are converted to chemical signals tocommunicate with effector cells or other nerve cells. By way of example,the delivery catheter 198 is capable of denervating a portion of anairway of the bronchial tree 27 to attenuate one or more nervous systemsignals transmitted by nerve tissue. Denervating can include damagingall of the nerve tissue of a section of a nerve trunk along an airway tostop substantially all of the signals from traveling through the damagedsection of the nerve trunk to more distal locations along the bronchialtree. If a plurality of nerve trunks extends along the airway, eachnerve trunk can be damaged. As such, the nerve supply along a section ofthe bronchial tree can be cut off. When the signals are cut off, thedistal airway smooth muscle can relax leading to airway dilation. Thisairway dilation reduces airflow resistance so as to increase gasexchange in the lungs, thereby reducing, limiting, or substantiallyeliminating one or more symptoms, such as breathlessness, wheezing,chest tightness, and the like. Tissue surrounding or adjacent to thetargeted nerve tissue may be affected but not permanently damaged. Insome embodiments, for example, the bronchial blood vessels along thetreated airway can deliver a similar amount of blood to bronchial walltissues and the pulmonary blood vessels along the treated airway candeliver a similar amount of blood to the alveolar sacs at the distalregions of the bronchial tree 27 before and after treatment. These bloodvessels can continue to transport blood to maintain sufficient gasexchange. In some embodiments, airway smooth muscle is not damaged to asignificant extent. For example, a relatively small section of smoothmuscle in an airway wall which does not appreciably impact respiratoryfunction may be reversibly altered. If the formulation at the desiredtemperature is used to destroy the nerve tissue outside of the airways,a therapeutically effective amount of the formulation does not reach asignificant portion of the non-targeted smooth muscle tissue.

As shown in FIGS. 2A and 2B, the delivery system 198 can include atreatment controller 202 and an intraluminal elongate assembly 200connected to the controller 202. The elongate assembly 200 can beinserted into the trachea 20 and navigated into and through thebronchial tree 27 with or without utilizing a delivery assembly. Theelongate assembly 200 can include a distal tip 203 capable ofselectively affecting tissue.

The controller 202 of FIG. 2A can include one or more processors,microprocessors, digital signal processors (DSPs), field programmablegate arrays (FPGA), and/or application-specific integrated circuits(ASICs), memory devices, buses, power sources, pump, formulationresources, vapor resources, liquid resources, contrast resources, vaporgenerator, desired temperature formulation generator, and the like.

The distal tip 203 of FIGS. 2A-2B can target various sites in the lungs10, including, without limitation, nerve tissue, fibrous tissue,diseased or abnormal tissues, muscle tissue, blood, blood vessels,anatomical features (e.g., membranes, glands, cilia, and the like), orother sites of interest.

FIG. 2C is a schematic view of a double balloon delivery catheterpositioned within a renal artery. The delivery catheter 106 of FIG. 2Ccan be used to treat hypertension. The formulation can be infused to thewall of the renal arteries adjacent to renal nerves for denervation.Some of the elements of the renal vascular system are omitted in FIG.2C.

In some embodiments, the catheter 10 disclosed herein allows for theformulation to be substantially homogeneous throughout the treatmentwindow 30 as shown in FIG. 3 . The position, diameter, number, andfrequency of lateral apertures 31 can result in the substantiallyhomogeneous filling of the treatment window 30. FIG. 3 depicts acatheter positioned in a body lumen 5 having two lateral apertures 31located within the treatment window 30 for the delivery of thetherapeutic agent 3. The lateral apertures 31 as shown in FIG. 3 are influid communication with the inner lumen 25. Lateral apertures 31located within the treatment window 30 can be in communication witheither the outer 24 or inner 25 lumen such that the formulation isdelivered homogeneously to the treatment window 30.

FIG. 4 is a schematic view of a double balloon delivery catheterpositioned within a pulmonary artery. The delivery catheter of FIG. 4can be used to treat pulmonary hypertension. The formulation can beinfused to the wall of the pulmonary arteries adjacent to nerves fordenervation. The front balloon of the depicted delivery catheter islocated at the bifurcation. A baseline pulmonary artery angiography canbe performed to identify the pulmonary artery bifurcation level andcalculate the artery diameter. An 8F long sheath is shown insertedthrough the femoral vein and advanced to the main pulmonary artery. Thedouble balloon catheter is advanced along the long shealth. The frontballoon is positioned at the bifurcation. The nerves near bifurcationare injured by ablation from the formulation infused by the deliverycatheter.

Some embodiments of the invention also include the step of deliveringthe formulation, such as vapor or liquid to the segment of the bodylumen at the delivery rate and for the determined duration. Theformulation may be heated to at least 80° C., or at least 100° C., or atleast 150° C. before delivering the formulations. The deliverycatheters, including the balloon and shafts, are functional when theformulations are at temperatures of at least 80° C., 100° C., or 150° C.The materials in the balloon and shafts of the catheters will sustainthese high temperatures. In some embodiments, delivering the vaporcauses the vapor to change to liquid, and the energy released during thephase change is transferred to the tissue of the segment or sub-segment.

In some embodiments, the safe and efficacious dosage for treating thetissue is between about 2 cal/g and about 150 cal/g., preferably betweenabout 5 cal/g and about 100 cal/g., and the energy flow rate of thedelivery system is between about 2 calories/second and about 500calories/second, preferable between about 5 cal/g and about 150 cal/g.In some embodiments, the generator can create a formulation, such asvapors or liquids, having a pressure between about 1 to 12 ATM psi at atemperature between about 20-150° C., preferable about 50-120° C.

Depending on the desired degree of injury for the tissues, a safe andefficacious amount of the formulation and/or energy, or dose of theformulation and/or energy (e.g., calories/gram), to be applied to thetissues can be determined to accomplish that result. In general, as thedose increases the degree of injury to the tissue increases. The desireddegree of injury to the tissues can therefore be controlled by alteringthe dose of formulations such as vapors or liquids at desiredtemperature applied to the tissues.

To be effective, the energy dose in preferred embodiments varies fromabout 1 cal/g to about 100 cal/g and/or the dose of the formulation insome embodiments varies from 0.2 microliter to 200 milliliters. Theselimits are, however, not intended to be definitive limitations of thedoses applied, as other delivery parameters described below (e.g.,delivery rate, delivery duration, etc.) may allow different doses to beapplied to accomplish the same or similar injury to the tissue.

After determining the dose to apply to the tissue, the amount of totalenergy or formulation that needs to be applied by a delivery system(such as the delivery system described in the invention) to the tissuecan be determined. This is done generally by multiplying the dose(cal/g) by the amount of tissue to be treated (grams) to determine theamount of formulation (ml) and energy (cals) to deliver.

The delivery (or flow) rate, or the rate at which the delivery systemdelivers the formulation, generally determines the duration that theformulation will be delivered to generate the determined amount ofenergy. For example, to deliver 300 calories to a segment of the lung ata delivery rate of 30 cals/second, the treatment duration would be 10seconds. The delivery rate is generally between about 2 cals/second toabout 200 cals/second. Again, these limitations are not intended to bedefinitive limitations and the delivery rate may be higher or lowerdepending on other treatment and/or delivery parameters.

Treatment times can vary depending on the volume, mass to be treated,and the desired injury to the tissue. Treatment times can vary fromabout 2 seconds to about 60 minutes. In some embodiments for causinginjury to relief symptoms, the safe and effective treatment time isbetween about 4 seconds and about 30 minutes.

The delivery rate can be set via controls of a delivery system. Once theuser sets the delivery rate, the formulation resources can establish therequisite amount of pressure to deliver the vapor or liquid at thedesired rate by adjusting the amount of pressure applied. Changing thedelivery rate setting will cause the generator to adjust the amount ofpressure in the generator. The pressure in the vapor generator can rangefrom between about 5 psi to over about 200 psi, preferable between about10 psi to over 50 psi.

In some embodiments, the method for treating hypertension includesinserting a delivery catheter percutaneously into the renal arteryadjacent to nerves; infusing a formulation described herein wherein at adesired temperature to the tissue of the body lumen adjacent to thenerves, wherein amount of the formulation and/or heat delivered iseffective to injure or damage the nerves to have a benefit, such aslower blood pressure; and withdrawing the delivery catheters from thebody lumen. The heat can be used to enhance the effect by acceleratingreaction rate of the formulation and the nerves. The formulations cancomprise gases, vapors, liquids, solutions, emulsion, or suspensions ofone or more ingredients. If the formulation comprises vapors of one ormore ingredients, the heat can be generated by condensation of thevapors into liquids in the tissue. If the formulation is liquids orsolutions, the heat can be transferred by the high temperatureformulations above body temperature. The desired temperature of theformulation can be in the range of −40 to 140° C., preferably −30 to100° C., most preferably −20 to 80° C. The temperature of the treatedtissue adjacent to the nerves can be lower than the desired temperatureof the formulation and higher than that of the body temperature. Thetemperature of the treated tissue adjacent to the nerves can be in therange of −40 to 100° C., preferably −30 to 90° C., most preferably −20to 80° C. The pressure of the formulation infused is higher than bodylumen pressure (1 ATM). The pressure range of the formulation infused tothe target tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM.

In some embodiments, the method for treating pulmonary arterialhypertension includes performing a pulmonary artery (PA) angiography toidentify the PA bifurcation level; inserting a delivery catheterpercutaneously through the femoral vein into the pulmonary arteryadjacent to nerves near PA bifurcation; locating the front balloon ofthe double balloon catheter at the bifurcation; infusing a formulationdescribed herein at a desired temperature to the tissue of the bodylumen adjacent to the nerves, wherein amount of the formulation and/orheat delivered is effective to injure or damage the nerves to have abenefit, such as lower blood pressure; and withdrawing the deliverycatheters from the body lumen. The heat can enhance the effect byaccelerating reaction rate of the formulation and the nerves. Theformulations can comprise gases, vapors, liquids, solutions, emulsion,or suspensions of one or more ingredients. If the formulation comprisesvapors of one or more ingredients, the heat can be generated bycondensation of the vapors into liquids in the tissue. If theformulation is liquids or solutions, the heat can be transferred by thehigh temperature formulations above body temperature. The desiredtemperature of the formulation can be in the range of −40 to 140° C.,preferably −30 to 100° C., most preferably −20 to 80° C. The temperatureof the treated tissue adjacent to the nerves can be lower than thedesired temperature of the formulation and higher than that of the bodytemperature. The temperature of the treated tissue adjacent to thenerves can be in the range of −40 to 100° C., preferably −30 to 90° C.,most preferably −20 to 80° C. The pressure of the formulation infused ishigher than body lumen pressure (1 ATM). The pressure range of theformulation infused to the target tissue is from 1 to 12 ATM, or 1 to 8ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the method for treating asthma includes inserting adelivery catheter into the airways adjacent to nerves; infusing aformulation described herein at desired temperature to the tissue of theairway adjacent to the nerves, wherein amount of the formulation and/orheat delivered is effective to injure or damage the nerves to have abenefit, such as relief of shortness of breath; and withdrawing thedelivery catheters from the body lumen. The heat can enhance the effectby accelerating reaction rate of the formulation and the nerves. Theformulations can comprise gases, vapors, liquids, solutions, emulsion,and suspensions of one or more ingredients. If the formulation comprisesvapors of one or more ingredients, the heat can be generated bycondensation of the vapors into liquids in the tissue. If theformulation comprises liquids or solutions, the heat can be transferredby the high temperature formulations above body temperature. The desiredtemperature of the liquid formulation can be in the range of −40 to 140°C., preferably −30 to 100° C. most preferably −20 to 80° C. Thetemperature of the treated tissue adjacent to the nerves can be lowerthan the desired temperature of the formulation and higher than that ofthe body temperature. The temperature of the treated tissue adjacent tothe nerves can be in the range of −40 to 100° C., preferably −30 to 90°C., most preferably −20 to 80° C. The pressure of the formulationinfused is higher than body lumen pressure (1 ATM). The pressure rangeof the formulation infused to the target tissue is from 1 to 12 ATM, or1 to 8 ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the method for treating COPD includes inserting adelivery catheter into the airway adjacent to nerves, infusing aformulation described herein at desired temperature to the tissue of thebody lumen adjacent to the nerves, wherein amount of the formulationand/or heat delivered is effective to injure or damage the nerves tohave a benefit, such as relief of COPD symptoms, and withdrawing thedelivery catheters from the airway. The heat can enhance the effect byaccelerating reaction rate of the formulation and the nerves. Theformulation can comprise gases, vapors, liquids, solutions, orsuspensions of one or more formulations. If the formulation comprisesvapors of one or more ingredients, the heat can be generated bycondensation of the vapors into liquids. If the formulation comprisesliquids or solutions, the heat can be transferred by the hightemperature formulations above body temperature. The desired temperatureof the formulation can be in the range of −40 to 140° C., preferably −30to 100° C., most preferably −20 to 80° C. The temperature of the treatedtissue adjacent to the nerves can be lower than the desired temperatureof the formulation and higher than that of the body temperature. Thetemperature of the treated tissue adjacent to the nerves can be in therange of −40 to 100° C., preferably −30 to 90° C., most preferably −20to 80° C. The pressure of the formulation infused is higher than bodylumen pressure (1 ATM). The pressure range of the formulation infused tothe target tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM.

In some embodiments, the method for treating obesity includes insertinga delivery catheter into the digestive lumen adjacent to nerves,infusing a formulation described herein at desired temperature to thetissue of the digestive lumen adjacent to the nerves, wherein amount ofthe formulation and/or heat delivered is effective to injure or damagethe nerves to have a benefit, such as lower body weight, and withdrawingthe delivery catheters from the digestive lumen. The heat can enhancethe effect by accelerating reaction rate of the formulations and thenerves. The formulations can comprise gases, vapors, liquids, solutions,emulsion and suspensions of one or more ingredients. If the formulationcomprises vapors of one or more ingredients, the heat can be generatedby condensation of the vapors into liquids. If the formulation comprisesliquids or solutions, the heat can be transferred by the hightemperature formulation above body temperature. The desired temperatureof the liquid formulation can be in the range of −40 to 140° C.,preferably −30 to 100° C., most preferably −20 to 80° C. The temperatureof the treated tissue adjacent to the nerves can be lower than thedesired temperature of the formulation and higher than that of the bodytemperature. The temperature of the treated tissue adjacent to thenerves can be in the range of −40 to 100° C., preferably −30 to 90° C.,most preferably −20 to 80° C. The pressure of the formulation infused ishigher than body lumen pressure (1 ATM). The pressure range of theformulation infused to the target tissue is from 1 to 12 ATM, or 1 to 8ATM or 1 to 5 ATM, preferred 1 to 3 ATM.

In some embodiments, the method for treating urological diseasesincludes inserting a delivery catheter into the urological lumenadjacent to nerves, infusing a formulation described herein at desiredtemperature to the tissue of the urological lumen adjacent to thenerves, wherein amount of the formulation and/or heat delivered iseffective to injure or damage the nerves to have a benefit, such ascontrol of urine flowing, and withdrawing the delivery catheters fromthe urological lumen. The heat can enhance the effect by acceleratingreaction rate of the formulation and the nerves. The formulations cancomprise gases, vapors, liquids, solutions, emulsions, and suspensionsof one or more ingredients. If the formulation comprises vapors of oneor more ingredients, the heat can be generated by condensation of thevapors into liquids. If the formulation comprises liquids or solutions,the heat can be transferred by the high temperature formulation abovebody temperature. The desired temperature of the liquid formulation canbe in the range of −40 to 140° C., preferably −30 to 100° C., mostpreferably −20 to 80° C. The temperature of the treated tissue adjacentto the nerves can be lower than the desired temperature of theformulation and higher than that of the body temperature. Thetemperature of the treated tissue adjacent to the nerves can be in therange of −40 to 100° C., preferably −30 to 90° C., most preferably −20to 80° C. The pressure of the formulation infused is higher than bodylumen pressure (1 ATM). The pressure range of the formulation infused tothe target tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM.

In some embodiments, the method for treating cancers or tumors includesinserting a needle or needle based delivery catheter percutaneously intothe cancers or tumors under image guidance; infusing a formulationdescribed herein at desired temperature to the cancer tissues of thehuman body, wherein amount of the formulation and/or heat delivered iseffective to injure or damage or eliminate the cancer tissues to have atherapeutic benefit, such as shrinking or eliminating tumors; andwithdrawing the delivery catheters from the body. The image guidance caninclude ultrasound, X-ray, CT scan, NMR imaging, scopes, or acombination thereof. Example cancers include adrenal, bladder, cervical,colon, esophageal, gallbladder, kidney, liver, lung, ovarian,pancreatic, prostatic, rectal, stomach, and uterine cancers. The heatcan be used to enhance the effect by accelerating reaction rate of theformulation and the cancer tissues. The formulations can comprise gases,vapors, liquids, solutions, emulsion and suspensions of one or moreingredients. If the formulation comprises vapors of one or moreingredients, the heat can be generated by condensation of the vaporsinto liquids. If the formulation comprises liquids or solutions, theheat can be transferred by the high temperature formulation above bodytemperature. The desired temperature of the formulation can be in therange of −40 to 140° C., preferably −30 to 100° C., most preferably −20to 80° C. The temperature of the treated tissue can be lower than thedesired temperature of the formulation and higher than that of the bodytemperature. The temperature of the treated tissue can be in the rangeof −40 to 100° C., preferably −30 to 90° C., most preferably −20 to 80°C. The pressure of the formulation infused is higher than body lumenpressure (1 ATM). The pressure range of the formulation infused to thetarget tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM.

In some embodiments, the method for treating pains includes inserting aneedle or needle based delivery catheter percutaneously into the tissueswith pains under image guidance; infusing a formulation described hereinat desired temperature to the pain tissues, especially back pains andcancer pains, of the human body, wherein the amount of formulationand/or heat delivered is effective to injure or damage or eliminate thenever tissues to have a therapeutic benefit, such as reducing oreliminating pains; and withdrawing the delivery catheters from the body.The image guidance can include ultrasound, X-ray, CT scan, NMR imaging,scopes, or a combination thereof. Example pains include head, arm,facial, lower limb, eye, jaw, scar, groin, adrenal, bladder, cervical,colon, esophageal, gallbladder, kidney, liver, lung, ovarian,pancreatic, prostatic, rectal, stomach, and uterine pains. The heat canbe used to enhance the effect by accelerating reaction rate of theformulation and the pain tissues. The formulations can comprise gases,vapors, liquids, solutions, emulsion and suspensions of one or moreingredients. If the formulation comprises vapors of one or moreingredients, the heat can be generated by condensation of the vaporsinto liquids. If the formulation comprises liquids or solutions, theheat can be transferred by the high temperature formulation above bodytemperature. The desired temperature of the formulation can be in therange of −40 to 140° C., preferably −30 to 100° C., most preferably −20to 80° C. The temperature of the treated tissue can be lower than thedesired temperature of the formulation and higher than that of the bodytemperature. The temperature of the treated tissue can be in the rangeof −40 to 100° C., preferably −30 to 90° C., most preferably −20 to 80°C. The pressure of the formulation infused is higher than body lumenpressure (1 ATM). The pressure range of the formulation infused to thetarget tissue is from 1 to 12 ATM, or 1 to 8 ATM or 1 to 5 ATM,preferred 1 to 3 ATM.

What is claimed is:
 1. A method of treating a disease, the methodcomprising: inserting a needle-based balloon delivery catheter into avascular lumen adjacent to a nerve, wherein the needle-based balloondelivery catheter comprises a balloon disposed along an elongated shaftand the balloon has a diameter in an inflated state in a range of from 2millimeters to 30 millimeters; inflating the balloon; infusing achemical formulation at a temperature and at a pressure from theneedle-based balloon delivery catheter adjacent to the nerve, wherein anamount of the chemical formulation delivered is effective to injure ordamage the nerve to have a benefit of relieving symptoms of the disease,wherein the chemical formulation is at least one of 10 wt % to 100 wt %ethanol and 1 wt % to 100 wt % acetic acid; deflating the balloon; andwithdrawing the needle-based balloon delivery catheter from the bodylumen, wherein the chemical formulation interacts with the nerveresulting in denervation; wherein the disease is chosen fromhypertension, diabetes, obesity, end-stage renal disease, heart failure,and a combination thereof.
 2. The method of claim 1, wherein thechemical formulation comprises at least one of a gas, vapor, liquid,solution, and an emulsion and/or suspension of one or more ingredients.3. The method of claim 1, wherein the temperature of the chemicalformulation is in the range of −40° C. to 140° C.
 4. The method of claim1, wherein the pressure of the formulation is in the range of 1 to 12ATM.
 5. The method of claim 1, wherein the pressure of the chemicalformulation is higher than the pressure of body lumen.
 6. The method ofclaim 1, wherein the amount of the chemical formulation is in the rangeof 0.2 microliters to 200 milliliters.
 7. The method of claim 1, whereinheat or energy is delivered from the chemical formulation adjacent tothe nerve in an amount from about 2 cal/g to about 150 cal/g.
 8. Themethod of claim 1, wherein the needle-based balloon delivery catheter isa balloon catheter, a double-balloon catheter, or a combination of aballoon catheter and an infusion catheter.
 9. The method of claim 1,wherein the chemical formulation further comprises a therapeutic agentfor nerve denervation, wherein the therapeutic agent is chosen fromsodium channel blockers, tetrodotoxin, saxitoxin, decarbamoyl saxitoxin,vanilloids, neosaxitoxin, lidocaine, conotoxins, cardiac glycosides,digoxin, glutamate, staurosporine, amlodipine, verapamil, cymarin,digitoxin, proscillaridin, quabain, veratridine, domoic acid, oleandrin,carbamazepine, aflatoxin, guanethidine, guanethidine sulfate, andcombinations thereof.
 10. The method of claim 1, wherein the chemicalformulation comprises a contrast agent for imaging nerve denervation.11. The method of claim 1, wherein the method is a method of thermal andchemical ablation for treating a disease, wherein the infusing of thechemical formulation from the needle-based balloon delivery catheteradjacent to the nerve comprises delivering the chemical formulation andenergy adjacent to the nerve, wherein the amount of energy and/orchemical formulation delivered is effective to injure or damage thenerve to relieve symptoms of the disease.
 12. The method of claim 11,wherein the energy is chosen from radiofrequency, cryoablation,microwave, laser, ultrasound, high intensity focused ultrasound, vaporcondensation of at least some of the chemical formulation to a liquid,and combinations thereof.
 13. The method of claim 11, wherein thechemical formulation is infused to the nerve tissue during, before, orafter the energy is delivered.
 14. The method of claim 11, wherein thechemical formulation comprises water or saline, wherein infusion of thechemical formulation from the needle-based balloon delivery catheteradjacent to the nerve is effective to decrease the temperature of thevascular lumen adjacent to the nerve.
 15. The method of claim 1, whereinthe chemical formulation is 100% ethanol.
 16. The method of claim 1,wherein the chemical formulation is an azeotrope of ethanol and water.17. The method of claim 1, wherein the needle-based balloon deliverycatheter further comprises a marker band located distally of theballoon.
 18. The method of claim 1, wherein the balloon comprises amaterial chosen from a polyamide, a nylon, a polyether block amide, apolyester, a polyethylene terephthalate, a polyurethane, a copolymerthereof, and a mixture thereof.
 19. A method of treating a disease, themethod comprising: inserting a needle-based balloon delivery catheterinto a vascular lumen adjacent to a nerve, wherein the needle-basedballoon delivery catheter comprises a balloon disposed along anelongated shaft and the balloon has a diameter in an inflated state in arange of from 2 millimeters to 30 millimeters; inflating the balloon;infusing a chemical formulation at a temperature and at a pressure fromthe needle-based balloon delivery catheter adjacent to the nerve, anddelivering heat and/or energy from the needle-based balloon deliverycatheter adjacent to the nerve, wherein an amount of the heat and/orenergy delivered combined with an amount of the chemical formulationdelivered is effective to injure or damage the nerve resulting indenervation of the nerve and relief of symptoms of the treated disease,wherein the chemical formulation is at least one of 10 wt % to 100 wt %ethanol and 1 wt % to 100 wt % acetic acid; deflating the balloon; andwithdrawing the needle-based balloon delivery catheter from the bodylumen; wherein the disease is chosen from hypertension, diabetes,obesity, end-stage renal disease, heart failure, and a combinationthereof.
 20. The method of claim 19, wherein the heat and/or energydelivered adjacent to the nerve is sufficient to bring the temperatureadjacent to the nerve to a range of −40° C. to 140° C.
 21. The method ofclaim 19, wherein the heat and/or energy delivered adjacent to the nerveis in an amount from about 2 cal/g to about 150 cal/g.
 22. The method ofclaim 19, wherein the energy is chosen from radiofrequency,cryoablation, microwave, laser, ultrasound, high intensity focusedultrasound, vapor condensation of at least some of the chemicalformulation to a liquid, and combinations thereof.
 23. The method ofclaim 19, wherein the needle-based balloon delivery catheter furthercomprises a marker band located distally of the balloon.
 24. The methodof claim 19, wherein the balloon comprises a material chosen from apolyamide, a nylon, a polyether block amide, a polyester, a polyethyleneterephthalate, a polyurethane, a copolymer thereof, and a mixturethereof.
 25. The method of claim 19, further comprising infusing achemical formulation comprising water or saline from the needle-basedballoon delivery catheter adjacent to the nerve to decrease thetemperature of the vascular lumen adjacent to the nerve.